Two neuroimmune communication pathways, the ascending vagus nerve and cells of the blood-brain barrier, have recently been identified to relay signals of peripheral infection to the brain by inducing the expression of IL-1 and TNF-alpha in the central nervous system (CNS). Chronic expression of IL-1 and TNF-alpha in the CNS, however, has been shown to contribute to the pathogenesis of many CNS diseases including chronic fatigue syndrome, AIDS dementia, and various neurodegenerative diseases. Whether chronic peripheral infection can cause CNS diseases by driving chronic production of IL-1 and TNF-alpha in the brain has not been studied. In a recently created infectious disease model, striking patterns of neuropathological changes were found in the brain without infiltration of either the pathogen or peripheral inflammatory cells into the brain parenchyma. The neuropathological changes were closely associated with the chronic expression of IL-1 and TNF-alpha in the brain. These pathological changes was enhanced by blocking the inhibitory mechanisms for IL-1 and TNF-alpha expression and reduced by intracerebral administration of specific antagonists of IL-1 and TNF-alpha. Therefore, it is hypothesized that induction of IL-1 and TNF-alpha in the brain by chronic peripheral infection is a mechanism for the pathogenesis of CNS diseases. Using this infectious disease model, the following specific aims are proposed to test this hypothesis: 1) Determine and characterize the neurotoxic effects mediated by chronic CNS production of IL-1 and/or TNF-alpha; and 2) Determine the role of glucocorticoids and prostaglandins in regulating the chronic expression of IL-1 and TNF-alpha in the brain. Specific Aim 1 is designed to characterize the neurotoxic effects attributable to the chronic expression of IL-1 and/or TNF-alpha in the brain induced by neuroimmune activation. In Aim 2, whether glucocorticoids and prostaglandins importantly controls the levels of chronic expression IL-1 and TNF-alpha and the manifestation of related neurotoxic effects in the brain will be determined. Glucocorticoids and prostaglandins are the two major feedback inhibitory regulators for IL-1 and TNF-alpha expression. Finally, the use of anti-inflammatory drugs in modulating the neurotoxic effects of chronic CNS production of IL-1 and TNF- alpha will also be evaluated in Specific Aim 2. This study will attempt to elucidate the mechanisms of neurotoxicity caused by chronic activation of the pathways for neuroimmune communication. The results will also provide critical information regarding the use of anti-inflammatory drugs for the treatment of CNS diseases.